The biological effect and the mode of action of the CXCL7-CXCL12 chemokine heterodimer

摘要

ABSTRACT Chemokines are essential in health and disease such as infections, autoimmune diseases, atherosclerosis, HIV/AIDS, and cancer. Many chemokines engage in heterophilic interactions with each other to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer- forming chemokines. The mode of action of chemokine heterodimers remains poorly understood. Previously, we identified all platelet-derived chemokines interacting with the two most abundant platelet chemokines, CXCL4 and CXCL7. The CXCL12 chemokine demonstrated strong heterodimerization with CXCL7. In the current project, we will determine the biological consequences of these new interactions and the mode of action of the CXCL7-CXCL12 heterodimer. In aim 1, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL12-mediated activities, that the CXCL7-CXCL12 heterodimer binds and activates the CXCL12’s receptor CXCR4, and the molecular mechanism underlying the effect of the CXCL12-based heterodimers on cell migration. In aim 2, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL7-mediated activities (neutrophil adhesion and migration) and the involvement of the CXCR2 receptor in CXCL7-CXCL12 heterodimer-mediated activities. The results of this project will deepen our understanding of chemokine biology and inform the future development of novel therapeutic intervention strategies exploiting heterophilic chemokine interactions.